JP2022522936A - Delivery of Tumor Treatment Electric Field (TTFIELDS) Using Implantable Transducer Array - Google Patents

Abstract

Tumor therapeutic electric fields (TTFields) can be delivered by implanting multiple implantable electrode element sets within the human body. Further, a temperature sensor positioned to measure the temperature by the electrode element is embedded together with a circuit for collecting the temperature measurement value from these temperature sensors. In some embodiments, an AC voltage generator configured to apply an AC voltage across multiple sets of electrode elements is further implanted in the human body.

Description

The present application claims benefits under US Provisional Patent Application No. 62 / 811,311 filed February 17, 2019. The entire provisional patent application is incorporated herein by reference.

TTFields (Tumor Treatment Electric Field) therapy is a proven approach for treating tumors. Referring to FIG. 1, in the prior art Optune® system for delivering TTFields, TTFields is directed to the patient via four converter arrays placed on the patient's skin in the immediate vicinity of the tumor. Will be delivered. These transducer arrays are configured in two pairs. One pair of them (A / A) is positioned on the left and right sides of the head and the other pair of them (B / B) is positioned on the front and back of the head. Each transducer array is connected to the AC voltage generator via a multi-wire cable. The AC voltage generator (a) sends AC current through one array pair during the first period and then (b) sends AC current through the other array pair during the second period. Then repeat steps (a) and (b) over the treatment period.

Each transducer array is configured as a set of capacitively coupled electrode elements (diameter about 2 cm) interconnected by flexible wires. Each electrode element comprises a ceramic disc sandwiched between a layer of conductive medical gel and an adhesive tape. When placed on the patient, the medical gel adheres to the contour of the patient's skin, ensuring good electrical contact between the body and the device. This adhesive tape holds the entire array in place on the patient even during daily activities of the patient.

The amplitude of the alternating current delivered through the transducer array is controlled so that the skin temperature (as measured on the skin under the transducer array) does not exceed the safety threshold of 41 ° C. Temperature measurements on the patient's skin are obtained utilizing several lower-placed thermistors within the disk of the transducer array. In existing Optune® systems, each array has eight thermistors with one thermistor positioned below each disk in the array (most arrays have nine or more disks, and each array has nine or more disks. Note that in that case the temperature measurement is performed only below a subset of the disks in the array).

Each thermistor in the four arrays is connected to an electronic device called a "cable box" via long wires. In this case, the temperature is measured from a total of 32 thermistors (4 arrays x 8 thermistors for each of the arrays A, A, B, and B), and analog / digital conversion is performed for each thermistor to a digital value. These measurements are then transmitted from the cable box to the AC voltage generator via two additional wires that facilitate bidirectional digital serial communication between the cable box and the AC voltage generator. The controller in the AC voltage generator utilizes these temperature measurements to deliver via each pair of arrays A, A, B, B to maintain a temperature below 41 ° C on the patient's skin. Control the current that will be. This current itself is delivered to each array via additional wires extending from the AC voltage generator to the arrays via the cable box (ie, one wire for each array).

The existing Optune® extends between four long 10-wire cables (each extending between each array and cable box) and between an AC voltage generator and cable box. There is one 8-wire spiral cord. Each 10-wire cable has 8 wires for carrying signals from 8 thermistas, 1 wire shared by all 8 thermistas, and for transmitting TTfields signals to the array. It has one wire and. The 8-wire spiral cord consists of one wire (Vcc) for supplying power to the cable box, one wire for grounding to the cable box, and two wires for data communication (AC). It has (for transmitting temperature readings to the voltage generator), four wires for the TTFields signal (ie, one for each of the four arrays).

U.S. Patent Application Publication No. 2018/0050200 U.S. Pat. No. 9910453

Dissanayake et al., "IFMBE proceding" vol. 23

One aspect of the invention relates to a first device for delivering a tumor therapeutic electric field. The first device comprises a plurality of electrode element sets, each of which is configured to be implanted in the human body. Further, the first device is configured to be embedded in a human body, and further includes a plurality of temperature sensors positioned with respect to the electrode element set so as to measure the temperature in each of the electrode element sets. In addition, the first device includes a circuit configured to be embedded in a human body and configured to collect temperature measurements from a plurality of temperature sensors. The first device also comprises an AC voltage generator configured to be implanted in the human body and to apply an AC voltage across a plurality of electrode element sets.

Some embodiments of the first device further comprise an inductively coupled circuit configured to be implanted in the human body and to feed an AC voltage generator.

Some embodiments of the first device further comprise a battery configured to be implanted in the human body and to power an AC voltage generator. Optionally, these embodiments may further comprise an inductively coupled circuit configured to be implanted in the human body and to charge the battery.

In some embodiments of the first device, each of the electrode element sets comprises a plurality of capacitively coupled electrode elements. Optionally, in these embodiments, each of the capacitively coupled electrode elements comprises a ceramic disc.

In some embodiments of the first device, each of the temperature sensors comprises a thermistor. In some embodiments of the first device, the plurality of electrode element sets, the plurality of temperature sensors, the circuit, and the AC voltage generator are all embedded in the human body.

Another aspect of the invention relates to a second device for delivering a tumor therapeutic electric field. This second device includes a plurality of electrode element sets, each of which is configured to be embedded in a human body. The second device also comprises a plurality of temperature sensors configured to be embedded in the human body and positioned to measure temperature in each of the electrode element sets. The second device also includes a circuit configured to be embedded in the human body and to collect temperature measurements from a plurality of temperature sensors.

In some embodiments of the second device, each of the electrode element sets comprises a plurality of capacitively coupled electrode elements. In some embodiments of the second device, each of the temperature sensors comprises a thermistor. In some embodiments of the second device, the plurality of electrode element sets, the plurality of temperature sensors, and the circuit are all embedded in the human body.

Another aspect of the invention relates to a third device for delivering a tumor therapeutic electric field. This third device includes a plurality of electrode element sets, each of which is configured to be embedded in a human body. Further, the third device includes a plurality of temperature sensors configured to be embedded in the human body and positioned to measure the temperature in each of the electrode element sets. The third device also comprises an AC voltage generator configured to be implanted in the human body and to apply an AC voltage across a plurality of electrode element sets.

Some embodiments of the third device further comprise an inductively coupled circuit configured to be implanted in the human body and fed to an AC voltage generator.

Some embodiments of the third device further comprise a battery configured to be implanted in the human body and to power an AC voltage generator. Optionally, these embodiments may further comprise an inductively coupled circuit configured to be implanted in the human body and to charge the battery.

In some embodiments of the third device, each of the electrode element sets comprises a plurality of capacitively coupled electrode elements. Optionally, in these embodiments, each of the capacitively coupled electrode elements may include a ceramic disc.

In some embodiments of the third device, each of the temperature sensors comprises a thermistor. In some embodiments of the third device, the plurality of electrode element sets, the plurality of temperature sensors, and the AC voltage generator are all embedded in the human body.

FIG. 3 is a block diagram of the prior art Option® used to deliver TTFields to the human head. FIG. 3 is a block diagram of an embodiment that reduces the number of conductors in each cable that must pass through the patient's skin. FIG. 3 is a block diagram of an embodiment in which both the transducer array and the hub are implanted in the patient's body. It is a diagram showing another approach using implantable electrodes, in which all of the electrodes, hubs, and AC voltage generators are implanted in the patient's body. It is a figure which shows the modification of the embodiment of FIG. 4 in which electric power is supplied to a hub and an AC voltage generator by using a wireless connection. It is a figure which shows one Embodiment which uses the embedded electrode which is powered by the embedded battery. It is a figure which shows one Embodiment which can switch the current to an individual electrode element on or off based on the state of an electric control switch set. FIG. 6 is a schematic diagram of a circuit suitable for mounting these switches in the embodiment of FIG.

Hereinafter, various embodiments will be described in detail with reference to the accompanying drawings. Similar reference symbols represent similar elements, and dashed lines represent the presence of embedded components.

Instead of using a transducer array positioned on the patient's skin to deliver TTFields (as in the embodiment of FIG. 1 above), the embodiments described herein are for delivering TTFields. Use a transducer array that is implanted in the patient's body. Embedding a transducer array can offer many potential benefits. These potential benefits are (1) hiding these arrays from the people involved with the patient, and (2) improving patient comfort (the array is positioned on the patient's skin). (By avoiding possible skin irritation, warmth, and / or restricted movement), (3) improved electrical contact between the converter array and the patient's body, (4) array. Eliminates the need to shave the area where the sac is located (because hair growth interferes with the delivery of TTFields), (5) avoids the risk of interruption of TTFields delivery due to the loss of the converter array. (6) The point at which the power required to deliver the TTfields is significantly reduced (eg, reducing the physical distance between the converter array and the tumor and bypassing high resistance anatomical structures such as the skull). (Due to), (7) the weight of the device that the patient must carry is significantly reduced (eg by using a smaller battery to take advantage of the reduced power requirements), (8) conversion. The point that possible skin irritation when the vessel array is positioned on the patient's skin is avoided, and (9) an anatomy that cannot be treated using the converter array positioned on the patient's skin. Anatomical structures (eg, the spinal cord, which is surrounded by highly conductive cerebrospinal fluid and further by the bone structure of the spinal column. Both the cerebrospinal fluid and the bone structure of the spinal column are permeation of TTFields into the spinal cord itself. Includes the ability to deliver TTFels to (interfere with).

In any of the embodiments described herein, a sensor (thermistor) for measuring temperature on or near the transducer array so that tissue temperature can be controlled and thermal damage to the tissue is avoided. Please note that it is important to have (etc.). If a given transducer array is composed of a plurality of individual elements (eg, ceramic disks), it is preferred to disperse the plurality of temperature sensors (eg, thermistors) within these plurality of individual elements.

One approach (not shown) for using implantable electrodes has a block diagram similar to that of FIG. 1 of the prior art described above, but with transducer arrays A, A, B, B. Both differ in that they are implanted within the patient's body (eg, between the scalp and the skull, or adjacent to the dura mater). This approach enjoys the advantages (1)-(8) described above, but also suffers many drawbacks. More specifically, each transducer array is a relatively long and bulky 10-lead cable extending out of the body through a surgical incision or port (AC voltage is applied to each transducer array). Connect to the cable box / AC voltage generator via one wire for the cable box and nine conductors used to obtain temperature readings from eight different locations on each converter array. Will be done. The use of this 10-lead cable can increase the bulk of the system. In addition, the inclusion of components that pass through the human skin and into the head increases the risk of infection, which can be a problem, especially in the case of the brain.

FIG. 2 shows an improved example of the approach described in the previous paragraph. This approach reduces the number of conductors in each cable that must pass through the patient's skin from 10 to 4, which significantly reduces the bulkiness and size of these cables. This can be achieved, for example, by implanting additional electrodes E adjacent to each of the embedded transducer arrays A, B and utilizing a hub-based architecture. When a hub-based architecture is used, each of the electronic blocks E is equipped with a multiplexer that reduces the number of leads required to obtain temperature measurements from nine to three, and the hub 30h is from each transducer array. It is used to collect temperature readings and transfer those readings to the AC voltage generator 30g. The AC voltage generator 30g can then control the current applied to each of the transducer array pairs A / A, B / B to ensure that overheating of the transducer array does not occur. An example of a circuit that can be used for mounting these electronic blocks E and hubs can be found in Patent Document 1 entitled "Temperature Measurement in Arrays for Delivering TTF Fields", which is hereby referred to in its entirety. Incorporate into. This embodiment reduces the size and bulkiness of the wire that must pass through the human skin, providing the advantages (1)-(8) described above, but passing through the human skin into the head. Does not mitigate the risk of infection associated with the components.

FIG. 3 shows a modified example of the approach of FIG. In the embodiment of FIG. 3, instead of positioning the hub outside the patient's body and extending four cables through the patient's skin (as in FIG. 2), the electronic device E, the transducer arrays A, B , And the hub 30h are implanted in the patient's body. In the embodiment of FIG. 3, only one cable (ie, the cable extending between the hub 30h and the AC voltage generator 30g) must pass through the patient's skin. Optionally, the cable is connectorized using the port 12 shown. In the example shown in FIG. 3, the hub 30h is positioned at any position in the patient's thorax, and the four four-lead cables are connected to the electronic device E in the patient's head and the converter arrays A and B. Extending in between, the hub 30h is located within the patient's thorax. This positioning is advantageous because the wire does not pass directly from the outside world into the patient's head, thus reducing the risk of serious infection. However, in a modification of the embodiment of FIG. 3, the hub 30h may be positioned within the patient's head, in which case the port 12 allowing access is also positioned within the patient's head. It will be.

In the embodiment of FIG. 3, the hub 30h collects temperature measurements from each of the converter arrays A and B via the electronic device E, and these temperature measurements are sent to the AC voltage generator 30 g via the port 12. To transfer. The AC voltage generator 30g may then control the current applied to each of the A / A, B / B pairs of the transducer array to ensure that overheating of the transducer array does not occur. .. In addition, this embodiment brings about the above-mentioned advantages 1 to 8.

FIG. 4 shows another approach using implantable electrodes and providing the advantages 1-8 described above. In this embodiment, the electrodes A, B, the hub 30h, and the AC voltage generator 30g are all implanted in the patient's body. Power for the hub 30h and the AC voltage generator 30g is supplied via a port 14 positioned at any location (eg, thoracic) on the patient's skin. The power source (eg, battery) of this embodiment is located externally, and the battery powers the hub 30h and the AC voltage generator 30g via the port. The port 14 is connected to the hub 30h and the AC voltage generator 30g via appropriate wiring (eg, two conductor cables).

In all embodiments in which the AC voltage generator 30 g is implanted in the patient's body (including the embodiment of FIG. 4), the power delivery on the order of 10 W to 100 W is required to effectively deliver the TTfields. Care must be taken to minimize heat dissipation. The reason for this is that any inefficiency can result in heating of the tissue surrounding the electric field generator, which can result in thermal damage to the tissue in the patient's body. To achieve this, the AC voltage generator 30g must operate with very high efficiency. An example of a circuit suitable for embedding a high-efficiency AC voltage generator is described in "High Voltage, High Voltage, High Efficiency Sine Wave Generator with Pre-Set Frequency and Amplitude and Patents, as a whole, the same as the patent". Is incorporated herein by reference.

Optionally, the AC voltage generator 30g in these embodiments may operate by starting from a low voltage AC signal and amplifying and filtering the signal using a circuit incorporating a transformer and an LC filter. In some embodiments, an independent circuit incorporating a transformer and an LC filter may be connected to each converter array (or even to each element of each transducer array). In these embodiments, the low voltage signal generator may be connected to each array (or element) via wires located remotely from the array. In this configuration, the heat generated by the loss in the system is diffused over a larger volume, reducing the risk of thermal damage to the tissue and allowing delivery of higher electric field strength. To further reduce the loss, the circuit on each array (or element) can be designed with a switch to switch between low voltage signals coming in and out of the signal generator. The loss in the system associated with the switchover in is potentially reduced.

Optionally, the power supply of the embodiment of FIG. 4 may include a plurality of small batteries woven into a piece of fabric. This type of design allows for longer delivery of high power while minimizing patient discomfort.

FIG. 5 shows an example of a modification to the embodiment of FIG. 4, which also brings about the above-mentioned advantages 1 to 8. In the embodiment of FIG. 5, the hub 30h and the AC voltage generator 30g are directly powered by a wired connection that passes from the outside world into the patient's body through a port 14 installed on human skin ( Instead (as in FIG. 4), in the embodiment of FIG. 5, power is supplied to the hub 30h and the AC voltage generator 30g using a wireless connection. This can be achieved, for example, by implanting the first circuit 21 in the patient's body near the patient's skin. The first circuit is configured to receive energy by inductively coupled. A second circuit 22 (optionally powered by a battery and / or an AC main) is configured to transmit energy to the first circuit 21 by inductively coupled. The second circuit 22 is positioned adjacent to the first circuit 21 outside the patient's body during operation so that energy can be inductively coupled from the second circuit 22 into the first circuit 21. .. The configurations of these circuits 21 and 22 for performing energy transmission / reception by inductively coupled are well known in the art and are generally used for charging mobile phones and the like, for example.

Optionally, the bulkiness and weight of the hardware that must be carried by the patient can be advantageously reduced by providing multiple copies of the second circuit 22 at various locations that the patient frequently visits. Become. For example, one copy of the second circuit 22 is provided in the patient's office, a second copy of the second circuit 22 is provided in the patient's vehicle, and a third copy of the second circuit 22 is in the patient's. A fourth copy of the second circuit 22 may be provided in the living room and may be provided in or near the patient's bed. If multiple copies of the second circuit 22 are provided, the patient can power any of the second circuits 22 in the vicinity to the AC voltage generator 30 g embedded by inductive coupling. The first circuit 21 embedded in the body is adjacent to the inductively coupled region where the circuit 22 of the second is located nearby. This configuration can be particularly advantageous for people who move in different patterns repeatedly (eg, drive to work in the same car every day, work at the same desk every day, rest in the same living room every night, and bed the same every night. People who sleep in, etc.). Optionally, multiple copies of the second circuit 22 may be incorporated within the mattress, allowing the patient to move around on the mattress without the need for wiring connections at bedtime.

FIG. 6 shows yet another embodiment using embedded electrodes that provides the advantages (1)-(8) described above. In particular, the battery 25 in the embodiment of FIG. 6 is implanted in the patient's body, and the implanted battery 25 is inductively charged. One difficulty with this design is that the embedded battery 25 must store a relatively large amount of energy. Therefore, inductive charging of the battery 25 requires the generation of a large magnetic flux over a long period of time. One way to solve this problem is in a system where a mattress with a built-in coil is used. The patient sleeps on this mattress and the battery 25 that powers the TTFields device is charged during the patient's sleep. In other embodiments, the coil may surround the bed.

Alternatively, a percutaneous energy transmission system (eg, see Non-Patent Document 1) may be used to charge the embedded battery 25. In this case, a coil connected to a circuit designed to charge the embedded battery is percutaneously embedded. Charging is performed using a separate device 24 placed near the coil 23 implanted by the patient. This external device may be secured to the patient's body using clothing designed to be in close contact with the body or using medical adhesives. The patient only needs to use an external charger to charge the embedded battery. This is done, for example, at night when the patient is sleeping, minimizing the need for the patient to carry an external device.

Optionally, the embedded transducer array device may be configured to allow dynamic changes in the electric field distribution to optimize TTFields delivery. Unlike the case of using external transducer arrays, these transducer arrays, once implanted, make it infeasible to adjust the position of the transducer arrays to optimize the electric field distribution within the patient's body. .. Therefore, when implantable arrays are used, another approach for controlling the electric field distribution within the patient's body is desirable. One suitable approach for this purpose is to embed a transducer array with a relatively large number of switchable elements. In this case, the electric field can be shaped by selecting a subset of array elements that can be switched on when the electric field is delivered. As the tumor changes over time (response or progression), it is possible to change the electric field distribution by changing the array element that generates the electric field.

Optionally, in any of the embodiments described above, the transducer array may be positioned on the dura. The advantage of this configuration is that the electric field does not have to pass through the high resistance layer of the skull, thus reducing the power required to deliver the TTfields to the brain. At the same time, this placement reduces the need for invasive placement of these arrays in the brain, reducing the risk of damage to brain tissue and, in some cases, the risk of infection. This configuration also allows delivery of TTFields to most of the brain, as opposed to delivering TTFields only to tumors. In some cases, it may be advantageous to treat most of the brain. For example, when treating the brain for metastasis. In some embodiments, when treating a body area other than the head, subcutaneous placement of the array may allow treatment of a large area. In other embodiments, the array may be placed in the vicinity of the tumor. Placement in the vicinity of the tumor allows for local delivery of TTFields and reduces the power required for electric field delivery.

In any of the embodiments described above, any component described as being implanted must be configured to be implanted prior to actual implantation into the human body. This means that this component must be sized to fit within the implantation position and that any surface that comes into contact with the tissue in the human body must be biocompatible.

Optionally, in any of the embodiments described above, when the transducer arrays are implanted in the immediate vicinity of the tumor, these arrays are made from or coated with a cytotoxic agent (eg, platinum). It is possible. Electrolysis caused by an electric field is expected to result in the release of platinum into the area around the tumor. Platinum is known to exert cytotoxicity against cancer cells, so release of platinum into tumors can advantageously increase the anti-cancer effect of TTFields treatment.

Optionally, in any of the embodiments described above, the transducer arrays A, B and electronic device E implanted in the human head can be designed as described below in connection with FIG. The advantage of this configuration is that the average electric field strength can be maximized and the heating risk is minimized by individually monitoring and adjusting the current to each electrode element in each transducer array, thereby delivering TTfields. The point is that efficiency can be improved. These embodiments operate by alternately switching the current on and off for each individual electrode element so that the individual electrode element does not affect the current passing through the remaining electrode elements. (These electrodes do not overheat.) Start overheating so as to reduce the average current of the electrode element.

For example, assume that a current of 500 mA is passing through a transducer array with 10 electrode elements and only one of those electrode elements begins to overheat. Further, it is assumed that it is necessary to reduce the current passing through this single electrode element by 10% in order to prevent the single electrode element from overheating. The embodiments described herein switch the current through this single electrode element on and off with a 90% duty cycle, while leaving the current full-time for all remaining electrode elements. By doing so, it becomes possible to reduce the average current passing through this single electrode element by 10%. It should be noted that the switching speed must be sufficient so that the instantaneous temperature of this single electrode element does not become excessively high in terms of the thermal inertia of the electrode element. For example, a 90% duty cycle can be achieved by switching the current on for 90 ms and off the current for 10 ms. In some preferred embodiments, the current on / off switching period is less than 1 s.

When this approach is used, the current passing through the remaining 9 electrode elements can remain unchanged (ie 50 mA per each electrode element) and passes through this single electrode element. Only the current is reduced to an average of 45 mA. In this case, the average net total current through the transducer array is 495 mA (ie 9 × 50 + 45), which means that significantly more current can be coupled to the human body without any of the electrode elements overheating. Means that.

In addition, the system may be configured to increase the current through the remaining nine electrode elements to compensate for the decrease in current through this single electrode element. For example, the current passing through the remaining nine electrode elements can be increased up to 50.5 mA per electrode element (eg, requesting the AC voltage generator to increase the voltage by 1%). By sending). When this solution is implemented, the average net total current through the entire transducer array is (9 electrodes x 50.5 mA + 1 electrode x 50.5 mA x 0.9 duty cycle) = 499.95 mA. This is very close to the original 500mA current.

If at some point later (or even simultaneously) the temperature of the second electrode element begins to overheat, a similar technique (ie, a duty cycle from 100% to less than 100%) (Decrease) can be utilized to prevent overheating of the second electrode element.

In some embodiments, the technique can be utilized to individually customize the duty cycle at each electrode element in order to maximize the current flowing through each electrode element without overheating. Optionally, instead of taking corrective action to reduce the duty cycle only if a given electrode element begins to overheat, the system is located to balance the temperature between all the electrode elements in the array. The duty cycle may be individually preset at each electrode element in the given converter array. For example, the system may be configured to individually set the duty cycle in each electrode element so as to maintain a temperature that remains near the set temperature of each electrode element. Optionally, the system may be configured to send a request to the AC voltage generator to raise or lower the voltage as needed to achieve this result.

This approach ensures that both electrode elements carry the maximum average current possible (without overheating), thereby increasing the electric field strength in the tumor and resulting in a corresponding improvement in treatment. Can be used for.

FIG. 7 shows an embodiment in which the current is periodically switched on / off for each individual electrode element that has begun to overheat. The hub / AC voltage generator 30 has two outputs (OUT1 and OUT2), each of which has two terminals. The hub / AC voltage generator 30 generates an AC signal (eg, a 200 kHz sine wave) between two terminals of each output in an alternating sequence (eg, in an alternating sequence, actuating OUT1 for 1 second and then actuating OUT2 for 1 second. Let). A pair of conductors 51 are connected to the two output terminals of OUT1 and each of these conductors 51 continues to one of the left and right transducer assemblies 31, 32, respectively. Each of these transducer assemblies has a plurality of electrode elements 52 (which collectively correspond to the transducer arrays A, B of FIGS. 2-6) and electronic components 56, 85 (which are FIGS. 2–6). (Corresponding to the electronic device E of 6). A second pair of conductors 51 are connected to the two terminals of OUT2, each of which leads to one of the anterior and posterior transducer assemblies (not shown). The structure and operation of the converter assemblies before and after this are the same as the structures of the left and right transducer assemblies 31 and 32 shown in FIG. 7.

Each transducer assembly 31, 32 comprises a plurality of electrode elements 52. In some preferred embodiments, each of these electrode elements 52 is a capacitively coupled electrode element. However, in the embodiment of FIG. 7, instead of wiring all of these electrode elements 52 in parallel, the electric control switch (S) 56 is wired in series with each electrode element (E) 52, and these S + E are wired. All combinations 56 + 52 are wired in parallel. Each switch 56 is configured to switch on / off independently of the other switches based on the state of each control input received from the digital output of each controller 85. If a given one of these switches 56 is on (in response to the first state of each control input), current can flow between the conductor 51 and each electrode element 52. Conversely, if a given one of these switches 56 is off (in response to a second state of each control input), the current will be between the conductor 51 and each electrode element 52. Can't flow.

In some preferred embodiments, each of the capacitive coupling electrode elements 52 is disk-shaped and has a dielectric layer on one side.

In some preferred embodiments, each of the capacitive coupling electrode elements 52 comprises a conductive plate having a flat surface, the dielectric layer being disposed on the flat surface of the conductive plate. In some preferred embodiments, all capacitively coupled electrode elements are held in place by the support structure. In some preferred embodiments, the electrical connection to each of the electrode elements 52 consists of wiring on a flexible circuit.

Further, each of the converter assemblies 31 and 32 includes a temperature sensor 54 (for example, a thermistor) positioned on each electrode element 52, whereby each temperature sensor 54 can sense the temperature of each electrode element 52. It becomes. Each temperature sensor 54 produces a signal representing the temperature at each electrode element 52 (eg, below it). These signals from the temperature sensor 54 are supplied to the analog front end of each controller 85.

In embodiments where the thermistor is used as the temperature sensor 54, the temperature reading can be obtained by sending a known current through each thermistor and measuring the voltage appearing between each thermistor. In some embodiments, thermistor-based temperature measurements may be performed using a bidirectional analog multiplexer to select each thermistor in sequence, with a current source producing a known current (eg, 150 μA). Positioned behind the multiplexer, it sends a known current to any thermistor selected by the analog multiplexer at any given moment. This known current produces a voltage across the selected thermistor, and the temperature of the selected thermistor can be determined by measuring this voltage. The controller 85 executes a program, which sequentially selects each thermistor and sequentially measures the voltage appearing across each thermistor (representing the temperature at the selected thermistor). An example of suitable hardware and procedures that can be used to obtain temperature readings from each thermistor is described in Patent Document 1, which is incorporated herein by reference in its entirety.

In some preferred embodiments, the controller 85 may be implemented using a single-chip microcontroller with an analog front end and a multiplexer or a Programmable System on Chip (PSoC). CY8C4124LQI-443 is mentioned as a part number suitable for this purpose. In an alternative embodiment, other microcontrollers with analog front ends and multiplexers that are either built-in or separate may be used, as will be apparent to those skilled in the art.

Although not shown, in an alternative embodiment, an alternative approach for linking to a thermistor (eg, a conventional voltage divider approach) may be utilized in place of the constant current approach described above. In other alternative embodiments, different types of temperature sensors may be used in place of the thermistors described above. Examples include thermocouples, RTDs, and integrated circuit temperature sensors such as Analog Devices AD590 and Texas Instruments LM135. Of course, if any of these alternative temperature sensors are used, appropriate modifications to the circuit (clear to those skilled in the art) will be required.

In some embodiments, the controller 85 is programmed to use the intelligence built into each transducer assembly 31 to keep the temperature at all electrode elements below the safety threshold. This can be achieved, for example, by programming the controller 85 to start by setting the digital output so that each switch 56 is continuously on (ie, 100% duty cycle). Then, based on the signal arriving via the analog front end of the controller 85, the controller 85 determines whether the temperature in each electrode element exceeds the threshold upper limit, which is less than the safety threshold. When the controller 85 detects this condition, the controller 85 reduces the duty cycle of the corresponding switch 56 by switching the corresponding digital output at the desired duty cycle. This interrupts the current to the corresponding electrode element 52 in the same duty cycle, thereby reducing the average current in the particular electrode element 52 having a temperature above the threshold upper limit. The level of current reduction is determined by the duty cycle. For example, using a 50% duty cycle reduces the current by half, and using a 75% duty cycle reduces the current by 25%.

In particular, this procedure interrupts only the current for a particular one of the electrode elements 52 on the transducer assembly 31, and does not interrupt the current for the remaining electrode elements 52 on the transducer assembly 31. This eliminates or reduces the need to cut off the current transmitted through these electrode elements when only a few of these electrode elements are hot.

Numerical examples may be useful in explaining this point. In the embodiment of FIG. 7, the left and right transducer assemblies 31, 32 are embedded in the left and right sides of the subject's head, respectively, and all switches 56 in the transducer assemblies 31, 32 are turned on in a 100% duty cycle. Suppose it is in a state and the hub / AC voltage generator 30 initially outputs a current of 500 mA to the conductor 51. A certain AC voltage appears between the electrode element 52 of the converter assembly 31 on the left side and the electrode element 52 of the converter assembly 32 on the right side, and an AC current of 500 mA passes through the electrode element 52 passing through the head of the subject. Capacitively coupled. The controller 85 in the transducer assemblies 31 and 32 monitors the temperature at each electrode element 52 in the transducer assembly by inputting a signal from each temperature sensor 54 via the analog front end of the controller 85. .. Next, assume that a given one of the electrode elements 52 in the transducer assembly 31 begins to overheat. This condition is reported to the controller 85 in the transducer assembly 31 via the signal from the corresponding temperature sensor 54. When the controller 85 recognizes that the given electrode element 52 is overheated, the controller 85 periodically interrupts the current to the given electrode element 52 to maintain a lower average current, which is desired. The control signal to advance to the corresponding switch 56 is switched in the duty cycle.

If the duty cycle in only one of the remaining electrode elements 52 is decreasing, it may be possible to maintain the original 500 mA current (and enjoy the benefits of using full current). Please note that. However, if the duty cycle of a sufficiently large number of electrode elements 52 is decreasing, it may be necessary to reduce the original current of 500 mA. To achieve this, the controller 85 can send a request to the hub / AC voltage generator 30 via the UART in the controller 85. When the hub / AC voltage generator 30 receives this request, the hub / AC voltage generator 30 reduces the output current at the corresponding output OUT1.

Optionally, the duty cycle selected by the controller 85 is measured by the rate at which the given electrode element 52 heats up after the application of current to the given electrode element 52 (by the temperature sensor 54 and the analog front end of the controller 85). Can be controlled based on (such as). More specifically, if the controller 85 recognizes that a given electrode element 52 is heating at twice the expected rate, the controller 85 has a duty cycle of 50% with respect to the electrode element. Can be selected. Similarly, if the controller 85 recognizes that a given electrode element 52 is heating 10% faster than expected, the controller 85 may select a duty cycle of 90% for that electrode element. ..

In another embodiment, instead of definitively reducing the average current by lowering the duty cycle, the controller 85 switches the current to the given electrode element 52 off and is measured using the temperature sensor 54. By waiting until the temperature drops below the second temperature threshold, the average current in a given electrode element 52 can be reduced based on real-time temperature measurements. When the temperature drops below this second temperature threshold, the controller 85 can restore the current to the given electrode element 52. This is because, for example, by controlling the state of the control input to the switch 56 that was previously switched off, the switch 56 returns to the ON state, whereby current can flow between the conductor and each electrode element 52. It may be realized by making it possible. In these embodiments, the current to the given electrode element 52 is iteratively turned on and off based on real-time temperature measurements to keep the temperature at the given electrode element 52 below the safety threshold. obtain.

In the embodiment of FIG. 7, each of the converter assemblies 31 and 32 is connected to the hub / AC voltage generator 30 via cables. In particular, only four conductors are required within each cable extending between the converter assembly and the hub / AC voltage generator 30 (ie, Vcc, data, and for implementing serial data communication). Grounding, as well as one additional lead for AC current TTFields signals 51).

Note that in FIG. 7, each transducer assembly 31, 32 comprises nine electrode elements 52, nine switches 56, and nine temperature sensors 54. However, in an alternative embodiment, each transducer assembly 31, 32 may include a different number of electrode elements 52 (eg, between 8 and 25) and a corresponding number of switches and temperature sensors. ..

In these embodiments, the duty cycle is adjusted to reduce the average current to one or more in the electrode element 52 or one or more of the switches 56 in a given transducer assembly 31, 32 is switched off. The determination is made locally within the transducer assemblies 31, 32 by the controller 85 within the transducer assemblies 31, 32. However, in an alternative embodiment, the decision to adjust the duty cycle or switch off one or more of these switches 56 is made by the hub / AC voltage generator 30 (or another remote device). It is also good. In these embodiments, the controller 85 in each of the converter assemblies 31 and 32 obtains a temperature reading from each temperature sensor 54 in each converter assembly and the hub / AC voltage via the UART of the controller 85. Send those temperature readings to the generator 30. The hub / AC voltage generator 30 toggles which switch needs it if there is a switch that needs to adjust the duty cycle, or if there is a switch that should be toggled off. It should be determined based on the received temperature reading and send the corresponding instruction to the corresponding controller 85 in the corresponding transducer assemblies 31, 32. When the controller 85 receives this command from the hub / AC voltage generator 30, the controller 85 responds by setting the digital output to a state in which the corresponding switch 56 is switched off in a timely manner, thereby the hub / AC. The instructions issued by the voltage generator 30 are implemented. In these embodiments, the hub / AC voltage generator 30 is programmed to reduce the output current if a current reduction is required to keep the temperature at each electrode element 52 below the safety threshold. It is also possible.

In these embodiments, the controller 85 may be programmed to act as a slave to a master controller located within the hub / AC voltage generator 30. In these embodiments, the controller 85 is started in a stationary state, in which case the controller 85 only monitors incoming and outgoing commands from the master controller arriving via the UART. Examples of instructions that can be received from the master controller include the "collect temperature data" instruction, the "send temperature data" instruction, and the "set switch" instruction. When the controller 85 recognizes that the "collect temperature data" command has arrived, the controller 85 acquires the temperature reading from each of the temperature sensors 54 and stores the result in the buffer. When the controller 85 recognizes that the "send temperature data" command has arrived, the controller 85 steps to send the previously collected temperature reading from the buffer to the hub / AC voltage generator 30 via the UART86. Run. Further, when the controller 85 recognizes that the "set switch" command has arrived, the controller 85 sets each switch 56 to a desired state (that is, based on the data received from the hub / AC voltage generator 30). Either ON, OFF, or switching between ON and OFF in the commanded duty cycle), perform the procedure to output the appropriate voltage at the digital output.

In the embodiments described above, a single controller 85 is used within the transducer assemblies 31, 32 to control the switch 56 within the assembly and the temperature from each temperature sensor 54 within the assembly. Get the measured value. In an alternative embodiment, instead of using a single controller 85 to control these switches 56 and obtain temperature readings, those two tasks are split between the two controllers, one controller , Used only to control the switch 56, the other controller may be used to obtain temperature measurements from each temperature sensor 54 (eg, utilizing any of the approaches described above). .. In these embodiments, these two controllers may communicate directly with each other and / or directly with the hub / AC voltage generator 30.

In another alternative embodiment (not shown), the temperature measurement is independent of the local controller positioned in the vicinity of the electrode element 52. Instead, wires extend from each temperature sensor 54 back to the hub / AC voltage generator 30, and the hub / AC voltage generator connects these wires to determine temperature at each temperature sensor 54. Use the signal that arrives via.

FIG. 8 is a schematic diagram of a circuit suitable for mounting the switches 56, 56'in the embodiment of FIG. 7 described above. This circuit includes two field effect transistors 66 and 67 wired in series, and is configured to allow current to flow in both directions. An example of a FET suitable for this circuit is the BSC320N20NSE (note that the diode shown in FIG. 8 is inherently contained within the FETs 66, 67 itself). The series combination of the two FETs 66, 67 either conducts or blocks current depending on the state of the control input arriving from one of the digital outputs of the controller 85 described above. When the combination in series is conductive, current can flow between the shared conductor 51 and the respective electrode elements 52, 52'. On the other hand, when the series combination of the FETs 66 and 67 is not conducting, the current does not flow between the shared lead wire 51 and the respective electrode elements 52 and 52'.

Optionally, the current sensing circuit 60 may be positioned in series with the switches 56, 56'. The current sensing circuit 60 can be implemented using any of a variety of conventional approaches that will be apparent to those skilled in the art of the art. When the current sensing circuit 60 is provided, the current sensing circuit 60 produces an output representing the current, which output is returned to the controller 85 and reported (shown in FIG. 7). The controller 85 can then use this information to determine if the measured current is as expected and take appropriate action if necessary. For example, if an overcurrent condition is detected, the controller 85 may toggle the corresponding switch off. Of course, in embodiments where the current sensing circuit 60 is omitted, the current sensing circuit 60 is wire (or other wire) so that it can flow between the conductor 51 on which the current is shared and the top leg of the upper FET 66. Should be replaced.

In the illustrated embodiment, the current sensing circuit 60 is positioned between the shared conductor 51 and the top leg of the upper FET 66. However, in an alternative embodiment, the current sensing circuit may be positioned between the bottom leg of the lower FET 67 and the respective electrode elements 52, 52'. In yet another alternative embodiment (not shown), the current sensing circuit may be incorporated within the circuit of the switch itself.

Although the invention has been disclosed with reference to some embodiments, numerous modifications, alternatives, to the embodiments described, without departing from the scope and scope of the invention as defined in the appended claims. And can be changed. Accordingly, the present invention is not limited to the embodiments described, but is intended to include the entire scope as defined by the words of the appended claims and their equivalents.

12 ports, 14 ports, 21 1st circuit, 22 2nd circuit, 23 coils, 24 devices, 25 batteries, 30 hubs / AC voltage generators, 30g AC voltage generators, 30h hubs, 31, 32 converter assemblies , 51 lead wire, 52 electrode element, capacitive coupling electrode element, 52'electrode element, 54 temperature sensor, 56 electronic component, electric control switch, 56' switch, 60 current sensing circuit, 66 upper FET, 67 lower FET, 85 electrons. Components, controller, OUT1 output, OUT2 output, A, B converter array, E electrode, electronic block, electronic device

Claims (20)

A device for delivering a tumor treatment electric field,
A plurality of electrode element sets, each of which is configured to be embedded in a human body, and a plurality of electrode element sets.
A plurality of temperature sensors configured to be embedded in the human body and positioned with respect to the electrode element set so as to measure temperature in each of the electrode element sets.
A circuit configured to be embedded in the human body and to collect temperature measurements from the plurality of temperature sensors.
An AC voltage generator configured to be implanted in the human body and to apply an AC voltage across the plurality of the electrode element sets.
A device equipped with. The apparatus according to claim 1, further comprising an inductively coupled circuit configured to be implanted in the human body and to supply power to the AC voltage generator. The device according to claim 1, further comprising a battery configured to be implanted in the human body and to supply power to the AC voltage generator. The device of claim 3, further comprising an inductively coupled circuit configured to be implanted in the human body and configured to charge the battery. The device according to claim 1, wherein each of the electrode element sets includes a plurality of capacitively coupled electrode elements. The apparatus according to claim 5, wherein each of the capacitive coupling electrode elements includes a ceramic disk. The device according to claim 1, wherein each of the temperature sensors includes a thermistor. The device according to claim 1, wherein the plurality of electrode element sets, the plurality of temperature sensors, the circuit, and the AC voltage generator are all embedded in the human body. A device for delivering a tumor treatment electric field,
A plurality of electrode element sets, each of which is configured to be embedded in a human body, and a plurality of electrode element sets.
A plurality of temperature sensors configured to be embedded in the human body and positioned to measure temperature in each of the electrode element sets.
A device comprising a circuit configured to be implanted in the human body and configured to collect temperature measurements from the plurality of temperature sensors. The device according to claim 9, wherein each of the electrode element sets includes a plurality of capacitively coupled electrode elements. The device of claim 9, wherein each of the temperature sensors comprises a thermistor. The device according to claim 9, wherein the plurality of electrode element sets, the plurality of temperature sensors, and the circuit are all embedded in the human body. A device for delivering a tumor treatment electric field,
A plurality of electrode element sets, each of which is configured to be embedded in a human body, and a plurality of electrode element sets.
A plurality of temperature sensors configured to be embedded in the human body and positioned to measure temperature in each of the electrode element sets.
A device comprising an AC voltage generator configured to be implanted in the human body and configured to apply an AC voltage across the plurality of the electrode element sets. 13. The apparatus of claim 13, further comprising an inductively coupled circuit configured to be implanted in the human body and to feed the AC voltage generator. 13. The device of claim 13, further comprising a battery configured to be implanted in the human body and to power the AC voltage generator. 15. The device of claim 15, further comprising an inductively coupled circuit configured to be implanted in the human body and configured to charge the battery. 13. The apparatus of claim 13, wherein each of the electrode element sets comprises a plurality of capacitively coupled electrode elements. 17. The apparatus of claim 17, wherein each of the capacitive coupling electrode elements comprises a ceramic disc. 13. The apparatus of claim 13, wherein each of the temperature sensors comprises a thermistor. 13. The device of claim 13, wherein the plurality of electrode element sets, the plurality of temperature sensors, and the AC voltage generator are all embedded in the human body.

Images